Formulation and process for drug loaded cores

ABSTRACT

The present invention relates to a controlled release pellet of metoprolol and its pharmaceutically acceptable salts that uses a water soluble or a water swellable inert starting seed or core.

This application is a continuation application of U.S. patentapplication Ser. No. 10/617,456, which was originally filed on Jul. 11,2003.

FIELD OF THE INVENTION

The present invention relates to the field of oral pharmaceutical dosageforms with controlled release of an active ingredient from a drug coreloaded with a high percentage of active ingredient. Specifically, thepresent invention relates to beta₁ adrenergic blocking agent pelletsthat are compressed into a tablet or loaded into a capsule shell, and amethod of preparation of such pellets wherein the pellets are comprisedof water soluble or water swellable inert starting seeds or cores. Morespecifically, the beta₁ adrenergic blocking agent is metoprolol.

BACKGROUND OF THE INVENTION

A constant time controlled and/or a pH specific release of the activecomponent of an orally administered drug is advantageous in medicaltreatment. The present invention relates to the oral administration ofdoses of metoprolol and its pharmaceutically acceptable salts such as,but not limited to, succinate, fumerate or benzoate of racemicmetoprolol and the benzoate or sorbate of the S-enantiomer of metoprololas disclosed in U.S. Pat. No. 4,957,745, U.S. Pat. No. 5,001,161 andU.S. Pat. No. 5,081,154 and incorporated herein by reference. Thetherapeutic effect of these drugs can be seen in the normalization ofblood pressure for hypertension sufferers, and in the reduction ofoxygen requirements in cardiac tissues, which induces beneficial affectson both angina pectoris and myocardial infarction.

Previously, inert cores for preparing controlled release forms ofmetoprolol pellets have been limited to water insoluble materials,because the use of water soluble materials combined with metoprololcreated a great amount of osmotic pressure causing the controlledrelease pellets to burst and dump the drug. See U.S. Pat. No. 4,927,640which is incorporated herein by reference.

SUMMARY OF THE INVENTION

The present invention solves the problems associated with the use of awater-soluble and/or water swellable cores for metoprolol controlledrelease pellets. The controlled release pellets are prepared by coatinga drug layer or layers onto a water soluble or water swellable inertstarting seed or core then applying over the drug layer a polymericcoating that controls the release of the drug. Said pellets are thenformed into an extended release tablet or capsule for oraladministration.

The controlled release pellets of the present invention are comprisedof:

-   -   a) a water soluble or water swellable inert core;    -   b) a drug layer comprising metoprolol or a pharmaceutically        acceptable salt thereof applied to the inert core; and    -   c) a controlled release coating surrounding the drug layer.

The pellets can be mixed with conventional tabletting excipients andcompressed into a tablet or loaded into a capsule for oraladministration.

The present invention also relates to a method of producing the pelletsor beads.

Additionally, the present invention relates to the formation of a tabletusing the controlled release pellets with and without additional activerelease pellets. The active release pellets being formed in the samemethod as the controlled release pellets, but without the controlledrelease coating.

In a preferred embodiment of the present invention an aqueous solventsystem is used instead of an organic solvent system to apply the druglayer to the inert core. This process is also more environmentallyfriendly due to the lack of conventional organic solvents such asmethylene chloride.

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, the inert core is a water soluble or waterswellable core. The inert core must be of sufficient density andstrength to enable it to undergo coating in a fluidized bed process. Theinert cores of the present invention should have a diameter less than 30mesh and preferably less than 40 mesh. In a preferred embodiment theinert cores should have a diameter ranging from about 30 to 200 mesh,preferably 40 to 120 mesh and most preferred 60 to 80 mesh.

Suitable water-soluble cores are sugar seeds or non-pareils that arewell known in the art. Examples of water swellable cores aremicrocrystalline cellulose spheres commercially available from FMCCorporation under the trade name CELPHERE®.

The pharmaceutically active ingredient or drug that is applied to theinert core is metoprolol or its pharmaceutically acceptable salts, suchas, succinate, fumarate, tartrate, citrate, pamoate, mandelate or othersthat are described in U.S. Pat. Nos. 4,281,654; 4,303,637; 4,957,745;5,001,161 and 5,081,154 which are incorporated herein by reference. Themetoprolol or its pharmaceutically acceptable salts may be in itsracemic form or a pure enantiomer, such as, the s-enantiomer of thebenzoate or sorbate salt. In one of the embodiments of the presentinvention it is preferred that the metoprolol used is micronized, so theaverage particle size is less than 100 microns, and preferably less than50 microns, and most preferably not less than 25 microns.

In order for the drug to be applied to the inert core, a binding agentmay be necessary. The binding agent employed in the active pellet can beany type of binding agent commonly known in the art. Examples of some ofthe preferred binding agents are polyvinyl pyrrolidone, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,polyacrylate, ethylcellulose, or mixtures of the foregoing. In thepreferred embodiment of the present invention, the binding agent is awater soluble or rapidly dispersible material, such as hydroxypropylmethylcellulose, or polyvinyl pyrrolidone.

The drug is applied to the inert core by any conventional techniquesknown in the industry, such as, pan coating, roto-granulation orfluidized bed coating. During such coating operations the drug isdispersed or dissolved in an organic or aqueous solvent, which may alsocontain other conventional excipients, such as the above mentionedbinding agent. In a preferred embodiment, an aqueous solvent isemployed. When the aqueous solvent is used, it may be necessary toinclude a surfactant in the solvent in order to keep the drug and otherexcipients suspended or dispersed.

If a surfactant is employed, it can be any type of surfactant commonlyknown in the art such as a fatty acid, a chelating agent, a bile salt ormixtures thereof. Examples of some preferred surfactants are fatty acidssuch as capric acid, oleic acid and their monoglycerides, especiallyalkyl sulfates, such as sodium lauryl sulfate, sodium dodecyl sulfateand polysorbate 80; chelating agents such as citric acid and phyticacid. The preferred surfactant used herein is polysorbate 80.

In a preferred embodiment of the present invention, the drug layercomprises the following ingredients: TABLE I Drug Layer IngredientsPreferred Most Preferred drug 50-100% 70-99% binder 0-50%  1-25%surfactant  0-1.0%   0-0.50%

The above weight percentages are based on the total weight of the activecoating layer.

Once the drug layer is applied to the inert core, a controlled releasecoat is applied to the drug layer. The controlled release coat isapplied so that it prevents or retards the release of the drug from thepellet. The controlled release coat is preferably comprised of apolymeric film forming polymer and may optionally contain conventionalprocessing aids such as emulsifiers, plasticizers, surfactants,lubricants or channeling agents.

The film forming polymers suitable for use in the controlled releasecoating are water insoluble polymers such as, ethylcellulose, celluloseacetate, cellulose propionate (lower, medium or higher molecularweight), cellulose acetate propionate, cellulose acetate butyrate,triacetate, cellulose acetate phathalate, cellulose triacetate,poly(methyl methacrylate), poly(ethyl methacrylate), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate),poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenylmethacrylate), poly(methyl acrylate), poly(isopropyl acrylate),poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethyleneacrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene)high density, poly(propylene), poly(ethylene terephthalate), poly(vinylisobutyl ether), poly(vinyl acetate), poly(vinyl chloride), chitin,chitosan, poly(anhydrides), poly(lactic acid), ploy(glycolic acid),poly(ortho esters), poly(lactide co-glycollide), poly(hydroxy butyrate)or polyurethane or a mixture thereof.

As used herein the term water insoluble polymer includes polymers thatare slightly permeable to water. A suitable polymer which is slightlypermeable to water is a polymer sold under the trade name Eudragit® RS.Eudragit® Polymers are polymeric lacquer substances based on arcylatesand methylarcylates.

The controlled release coating may be built up applying a plurality ofcoats of polymer solution or suspension to the drug core as hereinafterdescribed. The membrane solution or suspension contains the polymer(s)dissolved or suspended, respectively, in a suitable aqueous or organicsolvent or mixture of solvents, optionally in the presence of aconventional excipient.

The controlled release coating solution or suspension may be applied tothe active cores in a conventional coating pan as indicated or,alternatively, using an automated system such as a CF granulator, forexample a FREUND CF® granulator, a GLATT® fluidized bed processor, amodified ACCELA-COTA® or other suitably automated bead coatingequipment.

Suitable emulsifiers that can be used in the present invention are mayinclude, but are not limited to, phospholipids, polysorbate, propyleneglycol, poloxamer, glyceryl monostearate, other pharmaceuticalemulsifiers and/or mixtures thereof.

Suitable surfactants that may optionally be used in the presentinvention are sodium lauryl sulfate, sodium taurocholate or apolysorbate.

The controlled release coating may optionally include a plasticizingagent. Plasticizers are used to increase the resiliency of the finishedproduct from cracking and fracturing. Suitable plasticizing agentsinclude polyethylene glycol, propylene glycol, glycerol, triacetin,dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutylsebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate,castor oil, poloxamers and varying percentages of acetylatedmonoglycerides.

Suitable lubricants possess anti-sticking or anti-tacking properties.Suitable lubricants used in preparing solid dosage forms may includetalc, stearic acid, magnesium stearate, glyceryl monostearate, sodiumstearyl fumerate, hydrogenated oils, polyethylene glycols and sodiumstearate. A particularly preferred lubricant is talc.

A channeling agent is an excipient that is incorporated into thecontrolled release coating and functions to increase the volume of fluidimbibed into the core. It creates channels, preferably tortuous channelsthat enable gastric and intestinal fluid to enter the core and allow theactive compound to leave the core. The channeling agent can be a watersoluble material or an enteric material. Some examples of the preferredmaterials that are useful as channeling agents are sodium chloride,potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol(PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropylmethycellulose, hydroxypropyl methycellulose phthalate, celluloseacetate phthalate, polyvinyl alcohols, cellulose acetate butyrate,methacrylic acid copolymers, zein and mixtures thereof. The preferredchanneling agent is Eudragit® S100, a methacrylic acid copolymercommercially available from Rohm Pharma Gmbh.

The channeling agent may also be a water soluble drug. If the channelingagent is a drug, such as metoprolol, the present dosage form has theadded advantage of providing an immediate release of active component.

In a preferred embodiment of the present invention, the controlledrelease coating comprises the following ingredients: TABLE II ExtendedRelease Coating Ingredients Preferred Most Preferred water insoluble50-95%  75-90%  polymers emulsifier 0-25% 5-15% channeling agent 0-15%2-10%

The above weight percentages are based on the total weight of the newlyformed extended release coating layer.

Once the controlled release coat is applied to the active cores, aplurality of the pellets may be compressed into a tablet or filled intoa gelatin capsule, HPMCP capsule, HPMC capsule and/or pullulan capsule.The tablet forming processes preferably involves the mixing of thecontrolled release pellets with a disintegrant, a lubricant (orplasticizer) and a surfactant. The mixture is then compressed with acushioning agent into a tablet and optionally coated with a color,esthetic or polishing coat. Suitable cushioning agents include, but arenot limited to glyceryl monostearate, various grades of microcrystallinecellulose, lactose and mixtures thereof.

The controlled release pellets prepared in accordance with the presentinvention should exhibit the following dissolution profile when testedin a USP Type 2 apparatus, at 75 rpm, 37° C. and in a phosphate buffermedium with a pH of 7.5. TABLE III Time Preferred Most Preferred 2 hours0-40%  0-25% 4 hours 5-50% 10-45% 8 hours 25-80%  35-75% 16 hours  NLT50% NLT 75%NLT = not less than

Disintegrants used in the tabletting process are added to assist in thebreak down of the tablet. Suitable disintegrants are crospovidone XL-10,microcrystalline cellulose pH-102, microcrystalline cellulose pH-200,sodium starch glycolate and the like. The preferred disintegrant in thepresent invention is a mixture of crospovidone XL-10, microcrystallinecellulose pH-102 and microcrystalline cellulose pH-200.

Microcrystalline cellulose is added to improve the tabletting propertiesand assist in disintegration of the tablet in vitro. This in turn,assists in the release of the active pellets in the body. In a preferredembodiment, microcrystalline cellulose is used as a filler andcushioning agent. A cushioning agent is an excipient which facilitatescompression of pellets into a tablet or capsule, and helps protectcoated pellets from severe compaction forces and surface cracking.

Lubricants are used in the tabletting process to prevent the mixture ofcomponents from sticking to the equipment during the tabletting. Thelubricant also aids the ejection of the tablet from the dies, andadditionally may help improve powder flow. Suitable lubricants aredescribed above. The preferred lubricant in this step of the presentinvention is glyceryl monostearate. Additionally, lubricants providecushioning properties.

In a preferred embodiment of the present invention, the tablet comprisesthe following ingredients: TABLE IV Tabletting Ingredients PreferredMost Preferred Controlled Release Pellets 15-70%  25-50%Disintegrant/cushioning 5-70% 30-50% agent Lubricant 5-40%  5-30%

The above weight percentages are based on the total weight of the newlyformed tablet.

If an immediate release dose of the active ingredients is desired forthe final dosage form, the tablet or capsule may further comprise atherapeutically effective amount of the drug which can be mixed into thetablet excipient or with the controlled release pellets prior toencapsulation. In a preferred embodiment, the immediate release amountof the drug is provided by adding active drug pellets or pellets whichhave not been coated with the controlled release coating to thecontrolled release pellets prior to encapsulation or tabletting. In amore preferred embodiment of the present invention, a tablet will havethe following composition: TABLE V TABLETTING Ingredients Preferred MostPreferred Controlled Release Pellets 15-60% 25-45% Active Pellets  1-15%2-8% Disintegrant/Cushioning 20-70% 30-50% Agent Lubricant  5-40%  5-30%

The above weight percentages are based on the total weight of the newlyformed tablet, and the components are as described above.

A tablet or capsule containing the controlled release pellets preparedin accordance with the present invention and an immediate release formof metoprolol should exhibit the following dissolution profile whentested in a USP Type 2 apparatus at 75 rpm, 37° C. and in a phosphatebuffer medium with a pH of 7.5 TABLE VI Time Preferred Most Preferred 2hours  0-50% 10-40% 4 hours 10-60% 20-50% 8 hours 25-80% 35-75% 16hours  NLT 50% NLT 60%NLT = not less than

The tablet or capsule containing the controlled release pellets preparedin accordance with the present invention and containing an immediaterelease amount of the metoprolol should obtain its peak plasma levelwithin about 3 to 8 hours, preferably about 4.5 hours to about 7.5 hoursand have a C_(max) of less than 300 ng/ml, preferably less than 275ng/ml, and most preferably between 200 ng/ml and 275 ng/ml.

DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention will be further illustrated by the followingexamples

Example I

A controlled release metoprolol succinate tablet in accordance with thepresent invention is prepared as follows.

Stage I Drug Layering Process

0.7378 kg of hydroxypropyl methylcellulose (Methocel E-5) is dissolvedin 44.100 kg of purified water using a mechanical stirrer until a clearsolution is obtained. 14.775 kg of metoprolol succinate and 0.0205 kg ofTween 80 are then added into the solution. Once the drug is added, thesuspension should be constantly stirred until the spraying process iscompleted to avoid settling.

5.327 kg of sugar spheres NF 60/80 are placed into a fluidized bedcoater. The product air temperature of the coater should be higher than45° C. prior to loading the sugar spheres into the fluidized bed coater.The drug suspension prepared above is sprayed onto the sugar seeds usingthe following conditions: TABLE VII Nozzle tip diameter 1.2 mm ScreenSize 100 mesh Shaking interval 30 min Shaking Duration 3 sec AtomizationPressure 2.5 bar Inlet Air Temperature 50-100° C. Pump Rate 5-80 mL/minTubing Size 16 mm

Once the drug suspension has been consumed the pellets are dried for 10minutes or until the loss on drying (LOD) is less than 3%. Finally, thepellets are screened using 40 mesh and 80 mesh screens. The pelletsbetween the 40 and 80 mesh are collected.

Pellets may be dusted with an anti-sticking agent which may include, butwould not be limited to talc or silicon dioxide (commercially availableas Aerosil®).

Stage II Polymer Coating process for Metoprolol Succinate ER Pellets

A controlled release coating is prepared with the following composition:TABLE VIII Metoprolol Active Pellets Amount Per Batch (kg) CelluloseAcetate 2.0885 kg Butyrate, PG CAB 171-15 Poloxamer 188 NF, Lutrol0.2500 kg F-68 Eudragit ® S100 0.1488 kg

The controlled release coating is prepared by dissolving 2.0885 kg ofthe cellulose acetate butyrate, 0.1488 kg of the Eudragit® S100, and0.2500 kg of the Lutrol F-68 into a mixture of 5.500 kg of purifiedwater and 49.00 kg of acetone and stirred until the solution is clearusing a mechanical stirrer. The solution is then applied to active ordrug layered pellets prepared above in Stage I using a bottom sprayfluidized bed coater with the same parameters as described for theapplication of the drug layer in Stage I.

After the controlled release solution has been consumed the pellets aredried for 10 minutes or until the LOD is less than 3%. Finally, pelletsare screened through 25 and 80 mesh screens and the pellets between the25 and 80 mesh screens are collected.

Stage III Tabletting and Seal/Color Coating of Metoprolol Succinate ERTabs

A tablet in accordance with the present invention is prepared with thefollowing composition: TABLE IX Ingredients Amount per Batch (kg)Metoprolol Succinate 38.220 kg Controlled Release Pellets (Stage II)Metoprolol Active Pellets  4.998 kg (Stage I) Microcrystalline Cellulose11.312 kg (Avicel PH-102) Microcrystalline Cellulose 26.320 kg (AvicelPH-200) Crospovidone (XL-10), NF  3.150 kg Glyceryl Monostearate 21.000kg

The microcrystalline cellulose, crospovidone, metoprolol controlledrelease pellets prepared in Stage II above, and metoprolol activepellets prepared in Stage I above are added to a blender and mixed for15 minutes. The glyceryl monostearate is then added to the blender andblended for an additional 5 minutes. The resulting mixture is thencompressed into tablets.

The resulting tablet should have a hardness between 5-25 kp, with atarget of 15 kp.

The resulting tablet may optionally be seal coated using a seal coatsolution and a binder. In the present invention the seal coat is formedusing Opadry White and hydroxypropyl methylcellulose. The seal coatmaterials are dissolved in water and applied to tablets using layeringtechniques commonly known in the industry such as fluidized bed coating,rotor granulation or pan coating.

Example II

A controlled release metoprolol tablet in accordance with the presentinvention is prepared as follows.

Stage I Drug Layering Process

0.7378 kg of hydroxypropyl methylcellulose (Methocel E-5) is dissolvedin 44.100 kg of purified water using a mechanical stirrer until a clearsolution is obtained. 14.775 kg of metoprolol succinate and 0.0205 kg ofTween 80 are then added into the solution. Once the drug is added, thesuspension should be constantly stirred until the spraying process iscompleted to avoid settling.

5.327 kg of microcrystalline cellulose spheres, CELPHERE® CP-203, areplaced into a fluidized bed coater. The product air temperature shouldbe higher than 45° C. prior to loading the microcrystalline cellulosespheres into the fluidized bed coater. The drug suspension preparedabove is sprayed onto the microcrystalline cellulose spheres using theparameters set forth in Example I.

Once the drug suspension has been consumed, the pellets are dried for,10 minutes or until the loss on drying (LOD) is less than 3%. Finally,the pellets are screened using 40 mesh and 80 mesh screens. The pelletsbetween the 40 and 80 mesh screen are collected.

Stage II Polymer Coating Process for Metoprolol Succinate ER Pellets

A controlled release coating is prepared with the following composition:TABLE X Metoprolol Active Pellets Amount Per Batch (kg) CelluloseAcetate 2.0885 kg Butyrate, PG CAB 171-15 Poloxamer 188 NF, Lutrol0.2500 kg F-68 Eudragit ® S100 0.1488 kg

The controlled release coating is prepared by dissolving 2.0885 kg ofthe cellulose acetate butyrate, 0.1488 kg of the Eudragit® S100, and0.2500 kg of the Lutrol F-68 into a mixture of 5.500 kg of purifiedwater and 49.00 kg of acetone and stirred until the solution is clearusing a mechanical stirrer. The solution is then applied to the activeor drug layered pellets prepared above in Stage I using a bottom sprayfluidized bed coater with the same parameters as described for theapplication of the drug layer in Stage I.

After the controlled release solution has been consumed the pellets aredried for 10 minutes or until the LOD is less than 3%. Finally, pelletsare screened through 25 and 80 mesh screens and the pellets between the25 and 80 mesh screens are collected.

Stage III Tabletting and Seal/Color Coating of Metoprolol Succinate ERTabs

A tablet in accordance with the present invention is prepared with thefollowing composition. TABLE XI Ingredients Amount per Batch (kg)Metoprolol Succinate 38.220 kg Controlled Release Pellets (Stage II)Metoprolol Active Pellets  4.998 kg (Stage I) Microcrystalline Cellulose11.312 kg (Avicel PH-102) Microcrystalline Cellulose 26.320 kg (AvicelPH-200) Crospovidone (XL-10), NF  3.150 kg Glyceryl Monostearate 21.000kg

The microcrystalline cellulose, crospovidone, metoprolol controlledrelease pellets prepared in Stage II above, metoprolol active pelletsprepared in Stage I above are added to a blender and mixed for 15minutes. The glyceryl monostearate is then added to the blender andblended for an additional 5 minutes. The resulting mixture is thencompressed into tablets.

The resulting tablet should have a hardness between 5-25 kp, with atarget of 15 kp.

The resulting tablet may optionally be seal coated using a seal coatsolution and a binder. In the present invention the seal/color coat isformed using Opadry White and hydroxypropyl methylcellulose. The sealcoat materials are dissolved in water and applied to tablets usinglayering techniques commonly known in the industry such as fluidized bedcoating, rotor granulation or pan coating.

Example III

A controlled release metoprolol succinate tablet in accordance with thepresent invention is prepared as follows.

Stage I First Drug Layering Process

0.4438 kg of hydroxypropyl methylcellulose (Methocel E-5) is dissolvedin 26.500 kg of purified water using a mechanical stirrer until a clearsolution is obtained. 8.8620 kg of metoprolol succinate and 0.0112 kg ofTween 80 are then added into the solution. Once the drug is added, thesuspension should be constantly stirred until the spraying process iscompleted to avoid settling.

5.3270 kg of sugar spheres NF 60/80 are placed into a fluidized bedcoater. The product air temperature should be higher than 45° C. priorto the loading of the sugar spheres into the fluidized bed coater. Thedrug suspension prepared above is sprayed onto the sugar spheres usingthe parameters set forth in Example I.

Once the drug suspension has been consumed, the pellets are dried for 10minutes in the fluidized bed coater or until the loss on drying (LOD) isless than 3%.

Stage II Second Drug Layering Process

0.2940 kg of hydroxypropyl methylcellulose (Methocel E-5) is dissolvedin 17.600 kg of purified water using a mechanical stirrer until a clearsolution is obtained. 5.9130 kg of metoprolol succinate and 0.0093 kg ofTween 80 are then added into the solution. Once the drug is added to thesuspension, it should be stirred continuously until the spraying processis completed to avoid settling.

14.644 kg of metoprolol active pellets from Stage I are placed into afluidized bed coater. The product air temperature should be higher than45° C. prior to loading the metoprolol active pellets into the fluidizedbed coater. Begin spraying the drug suspension prepared in Stage IIabove using the parameters set forth in Example I.

Once the drug suspension has been consumed the pellets are dried for 10minutes or until the loss on drying (LOD) is less than 3%. Finally, thepellets are screened using 40 mesh and 80 mesh screens. The pelletsbetween the 40 and 80 mesh are collected.

Stage III Polymer Coating Process for Metoprolol Succinate ER Pellets

A controlled release coating is prepared with the following composition:TABLE XII Metoprolol Active Pellets Amount Per Batch (kg) CelluloseAcetate 2.0885 kg Butyrate, PG CAB 171-15 Poloxamer 188 NF, Lutrol0.2500 kg F-68 Eudragit ® S100 0.1488 kg

The controlled release coating is prepared by dissolving 2.0885 kg ofthe cellulose acetate butyrate, 0.1488 kg of the Eudragit® S100, and0.2500 kg of the Lutrol F-68 into a mixture of 5.500 kg of purifiedwater and 49.00 kg of acetone and stirred until the solution is clearusing a mechanical stirrer. The solution is then applied to active ordrug layered pellets prepared above in Stage II using the bottom sprayfluidized bed coater with the same parameters as described for theapplication of the drug layer in Stage I.

After the controlled release solution has been consumed the pellets aredried for 10 minutes or until the LOD is less than 3%. Finally, pelletsare screened through 25 and 80 mesh screens and the pellets between the25 and 80 mesh screens are collected.

Stage IV Tabletting and Seal/Color Coating of Metoprolol Succinate ERTabs

A tablet in accordance with the present invention is prepared with thefollowing composition: TABLE XIII Ingredients Amount per Batch (kg)Metoprolol Succinate 38.220 kg Controlled Release Pellets (Stage III)Metoprolol Active Pellets  4.998 kg (Stage I) Microcrystalline Cellulose11.312 kg (Avicel PH-102) Microcrystalline Cellulose 26.320 kg (AvicelPH-200) Crospovidone (XL-10), NF  3.150 kg Glyceryl Monostearate 21.000kg

The microcrystalline cellulose, crospovidone, metoprolol controlledrelease pellets prepared in Stage III above, and metoprolol activepellets prepared in Stage II above are added to a blender and mixed for15 minutes. The glyceryl monostearate is then added to the blender andblended for an additional 5 minutes. The resulting mixture is thencompressed into tablets.

The resulting tablet should have a hardness between 5-25 kp, with atarget of 15 kp.

The resulting tablet may optionally be seal coated using a seal/colorcoat solution and a binder. In the present invention the seal coat isformed using Opadry White and hydroxypropyl methylcellulose. The sealcoat materials are dissolved in water or alcohol and applied to tabletsusing layering techniques commonly known in the industry such asfluidized bed coating, rotor granulation or pan coating.

Example IV

A controlled release metoprolol tablet in accordance with the presentinvention is prepared as follows.

Stage I Drug Layering Process

0.810 kg of hydroxypropyl methylcellulose (Methocel E-5) is dissolved in48.800 kg of purified water using a mechanical stirrer until a clearsolution is obtained. 16.200 kg of metoprolol succinate and 0.0210 kg ofTween 80 are then added into the solution. Once the drug is added, thesuspension should be constantly stirred until the spraying process iscompleted to avoid settling.

6.849 kg of sugar spheres, are placed into a fluidized bed coater. Theproduct air temperature should be higher than 45° C. prior to loadingthe microcrystalline cellulose spheres into the fluidized bed coater.The drug suspension prepared above is sprayed onto the sugar spheresusing the parameters set forth in Example I.

Once the drug suspension has been consumed, the pellets are dried for 10minutes or until the loss on drying (LOD) is less than 3%. Finally, thepellets are screened using 40 mesh and 80 mesh screens. The pelletsbetween the 40 and 80 mesh screen are collected.

Stage II Polymer Coating Process for Metoprolol Succinate ER Pellets

A controlled release coating is prepared with the following composition:TABLE XIV Metoprolol Active Pellets Amount Per Batch (kg) CelluloseAcetate  2.992 kg Butyrate, PG CAB 171-15 Poloxamer 188 NF, Lutrol0.3564 kg F-68 Eudragit ® S100 0.2138 kg

The controlled release coating is prepared by dissolving 2.992 kg of thecellulose acetate butyrate, 0.2138 kg of the Eudragit® S100, and 0.3564kg of the Lutrol F-68 into a mixture of 7.125 kg of purified water and64.12 kg of acetone and stirred until the solution is clear using amechanical stirrer. The solution is then applied to active or druglayered pellets prepared above in Stage I using a bottom spray fluidizedbed coater with the same parameters as described for the application ofthe drug layer in Stage I.

After the controlled release solution has been consumed the pellets aredried for 10 minutes or until the LOD is less than 3%. Finally, pelletsare screened through 40 and 80 mesh screens and the pellets between the40 and 80 mesh screens are collected.

Stage III Tabletting and Seal/Color Coating of Metoprolol Succinate ERTabs

A tablet in accordance with the present invention is prepared with thefollowing composition. TABLE XV Ingredients Amount per Batch (kg)Metoprolol Succinate 47.498 kg Controlled Release Pellets (Stage II)Metoprolol Active Pellets  3.856 kg (Stage I) Microcrystalline Cellulose38.961 kg (Avicel PH-102) Microcrystalline Cellulose 38.961 kg (AvicelPH-200) Crospovidone (XL-10), NF  4.374 kg Glyceryl Monostearate 12.150kg

The microcrystalline cellulose, crospovidone, metoprolol controlledrelease pellets prepared in Stage II above, metoprolol active pelletsprepared in Stage I above are added to a blender and mixed for 15minutes. The glyceryl monostearate is then added to the blender andblended for an additional 5 minutes. The resulting mixture is thencompressed into tablets.

The resulting tablet should have a hardness between 5-25 kp, with atarget of 15 kp.

The resulting tablet may optionally be seal coated using a seal coatsolution and a binder. In the present invention the seal coat is formedusing Opadry White and hydroxypropyl methylcellulose. The seal/colorcoat materials are dissolved in water and applied to tablets usinglayering techniques commonly known in the industry such as fluidized bedcoating, rotor granulation or pan coating.

Example V

A controlled release metoprolol tablet in accordance with the presentinvention and possessing the following ingredients in mg/unit isprepared as follows:

Stage I Drug Layering Process

A metoprolol active pellet is prepared comprising 38.05 mg/unit of a60/80 mesh sugar sphere layered with a drug layer comprising 9.5 mg/unitof hydroxypropyl methylcellulose (Methocel E-5), 190 mg/unit metoprololsuccinate and 0.25/unit mg of Tween 80. The drug layer is applied to thesugar sphere from an aqueous suspension of the drug layer ingredientsusing a fluidized bed coater.

Stage II Polymer Coating Process for Metoprolol Succinate ER Pellets

A controlled release coating is applied to 237.8 mg/unit of metoprololactive pellets, said coating comprising 75.77 mg/unit cellulose acetatebutyrate (PG CAB 171-15); 9.02 mg/unit of Poloxamer 188 NF, (LutrolF-68); and 5.41 mg/unit of methacrylic acid copolymer (Eudragit® S-100).The controlled release coating ingredients are dissolved in an wateracetone mixture and applied to the active pellets using a fluidized bedcoater.

Stage III Tabletting and Seal/Color Coating of Metoprolol Succinate ERTabs

A tablet is then formed comprising 295.2 mg/unit metoprolol ER pellets,23.78 mg/unit metoprolol active pellets, 239.51 mg/unit microcrystallinecellulose (Avicel PH-102), 239.51 mg/unit microcrystalline cellulose(Avicel PH-200), 75 mg/unit glyceryl monostearate 600P (and/or Myverol18-06 PK) and 27 mg/unit Crospovidone (XL-10).

The resulting tablet may optionally be seal coated using a seal/colorcoat solution and a binder. In the present invention the seal coat isformed using 20 mg/unit of Opadry White and 5 mg/unit of Opadry Clear.

While certain preferred and alternative embodiments of the inventionhave been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, the appended claims are intended tocover all embodiments of the invention and modifications thereof whichdo not depart from the spirit and scope of the invention.

1. A controlled release pellet comprising: a) an inert core that iswater soluble b) a drug layer applied to the inert core comprising: i) ametoprolol succinate, and ii) optionally a binder; c) a controlledrelease coating surrounding the drug layer wherein said coatingcomprises i) a water insoluble film forming polymer; ii) optionally achanneling agent; and iii) optionally an emulsifier.
 2. (canceled) 3.(canceled)
 4. (canceled)
 5. (canceled)
 6. (canceled)
 7. (canceled) 8.(canceled)
 9. A controlled release pellet as defined in claim 1, whereinthe inert core is a sugar seed.
 10. (canceled)
 11. (canceled)
 12. Thecontrolled release pellet as defined in claim 1, wherein the binder isselected from the group consisting of polyvinyl pyrrolidone,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyacrylate, ethylcellulose, or mixtures of thethereof.
 13. (canceled)
 14. The controlled release pellet as defined inclaim 1, wherein the drug layer further comprises a surfactant. 15.(canceled)
 16. (canceled)
 17. (canceled)
 18. The controlled releasepellet as defined in claim 1, wherein the water insoluble film-formingpolymer is selected from the group consisting of cellulose acetate,cellulose acetate butyrate, ethyl cellulose, hydroxypropyl celluloseacetate, hydroxypropyl methylphthalate and cellulose acetate phthalateor mixtures thereof.
 19. (canceled)
 20. (canceled)
 21. (canceled) 22.(canceled)
 23. (canceled)
 24. (canceled)
 25. (canceled)
 26. (canceled)27. The controlled release pellet as defined in claim 1, wherein thecontrolled release coating further comprises a plasticizer. 28.(canceled)
 29. An oral pharmaceutical tablet that comprises thecontrolled release pellet as defined in claim
 1. 30. An oralpharmaceutical capsule that comprises the controlled release pellet asdefined in claim
 1. 31. The controlled release pellet defined in claim 1that exhibits the following dissolution profile when tested in a USPType 2 apparatus at 75 rpm and 37° C. in a phosphate buffer with a pH of7.5, 0-40% of the metoprolol is released after 2 hours; 5-50% of themetoprolol is released after 4 hours; 25-80% of the metoprolol isreleased after 8 hours; not less than 50% of the metoprolol is releasedafter 16 hours.
 32. (canceled)
 33. The oral pharmaceutical tablet thatis defined in claim 29 that further comprises an immediate release formof metoprolol.
 34. The oral pharmaceutical capsule that is defined inclaim 30 that further comprises an immediate release form of ametoprolol.
 35. The oral pharmaceutical tablet as defined in claim 33that exhibits the following dissolution profile when tested in a USPType 2 apparatus at 75 rpm and 37° C. in a phosphate buffer with a pH of7.5, 0-50% of the metoprolol is released after 2 hours; 10-60% of themetoprolol is released after 4 hours; 25-80% of the metoprolol isreleased after 8 hours; not less than 50% of the metoprolol is releasedafter 16 hours.
 36. (canceled)
 37. The oral pharmaceutical capsule asdefined in claim 34 that exhibits the following dissolution profile whentested in a USP Type 2 apparatus at 75 rpm and 37° C. in a phosphatebuffer with a pH of 7.5, 0-50% of the metoprolol is released after 2hours; 10-60% of the metoprolol is released after 4 hours; 25-80% of themetoprolol is released after 8 hours; not less than 50% of themetoprolol is released after 16 hours.
 38. (canceled)
 39. Thepharmaceutical tablet as defined in claim 33 that exhibits a peak plasmalevel between 3 and 8 hours after administration.
 40. (canceled)
 41. Thepharmaceutical capsule as defined in claim 34 that exhibits a peakplasma level between 3 and 8 hours after administration.
 42. (canceled)43. (canceled)
 44. (canceled)
 45. The pharmaceutical tablet as definedin claim 41 that exhibits a C_(max) of between 200 ng/ml and 275 ng/ml.46. (canceled)
 47. (canceled)
 48. The pharmaceutical capsule as definedin claim 45 that exhibits a C_(max) of between 200 ng/ml and 275 ng/ml.49. A controlled release pellet consisting essentially of: a) an inertcore that is water soluble b) a drug layer applied to the inert corecomprising: i) metoprolol succinate; ii) a binder; and iii) optionally asurfactant; c) a controlled release coating surrounding the drug layercomprising: i) a water insoluble film forming polymer; ii) a channelingagent; and iii) optionally an emulsifier.
 50. (canceled)
 51. (canceled)52. (canceled)
 53. A controlled release pellet as defined in claim 49,wherein the inert core has a diameter of about 30 to 200 mesh. 54.(canceled)
 55. (canceled)
 56. (canceled)
 57. A controlled release pelletas defined in claim 49, wherein the inert core is a sugar seed. 58.(canceled)
 59. (canceled)
 60. An oral pharmaceutical tablet thatcomprises the controlled release pellet as defined in claim
 49. 61. Anoral pharmaceutical capsule that comprises the controlled release pelletas defined in claim
 49. 62. The oral pharmaceutical tablet that isdefined in claim 60 that further comprises an immediate release form ofmetoprolol.
 63. The oral pharmaceutical capsule that is defined in claim61 that further comprises an immediate release form of metoprolol.
 64. Aprocess for preparing a controlled release metoprolol succinate pelletcomprising: a) dissolving or suspending metoprolol succinate in anaqueous medium; b) applying the aqueous medium with the dissolved orsuspended metoprolol succinate onto a water soluble inert core to createa drug layer on the inert core; c) applying a controlled release coatingto the drug layer; wherein said wherein said coating comprises i) awater insoluble film forming polymer; ii) a channeling agent; and iii)optionally an emulsifier.
 65. (canceled)